Inflammation is a normal, homeostatic response to injury and infection. The Systemic Inflammatory Response Syndrome (SIRS), also called sepsis, results in a prolonged, abnormal and unbalanced inflammatory response that is pathologic. Sepsis is the leading cause of death in surgical intensive care units. One aspect of this syndrome is hepatic dysfunction. We have shown that this dysfunction involves a decrease in the transcription of important, liver-specific genes. The septic response is believed to be mediated in part by cytokines such as interleukin (IL)-6, but the specific role of IL-6 in modulating hepatic dysfunction and mortality is unknown. Using a well-characterized model of sepsis, cecal ligation and puncture (CLP) in the mouse, we will examine how IL-6 modulates hepatic dysfunction and mortality. To examine hepatic dysfunction, we will investigate seven important hepatic enzymes (phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, carnitine palmitoyltransferase II, acetyl CoA acyltranferase, ornithine transcarbmaylase, the Na-dependent taurocholate co-transporter and the canilicular conjugate export pump) whose transcription is known to be decreased in sepsis. Transcription will be investigated in IL-6+/+ and IL-6-/- mice following mild sepsis (single puncture CLP). To determine the effect of IL-6 on outcome, we will look at investigate mortality in IL-6+/+ and IL-6-/- mice following lethal sepsis (double puncture CLP). These studies will further our understanding of the hepatic component of SIRS/sepsis and of the contribution of IL-6 to outcome. Our finding may well have implications for the human disease.